The insulin-like growth factors (IGFs) are clearly involved in maintaining and stimulating breast tumor cell growth, and are therefore potential targets for therapeutic attach in the treatment of breast cancer. The IGF system comprises several elements: two growth factors (IGF-I and IGF-II), two receptors (IGFR-I and IGFRI-II) which both may mediate the growth-stimulating actions of IGF-I and IGF-II, and at least six IGF binding proteins (IGFBPs), which may either enhance or interfere with tumor growth stimulation. In order to target the IGF system effectively, it will be necessary to define the key elements of the system involved in growth regulation, as well as to demonstrate that specifically attacking these elements can inhibit breast cancer growth. We therefore propose three specific aims: (1) To inhibit IGF-stimulated breast cancer cell growth by blocking the expression of the IGFR-I using antisense strategies and by overexpressing a non-functional mutant receptor, (2) To define the role of IGFR-II in breast cancer cell growth by over-expressing it (using inducible promoters), and to determine the effects of the manipulation on basal and IGF-stimulated growth; (3) To investigate the -expression and function of the IGF binding proteins (IGFBPs) in breast cancer cells and clinical breast tumor specimens. It is well established that polypeptide growth factors are important regulators in cancer cell growth in vitro and that interference with growth factor pathways can lead to inhibition of tumor proliferation in many different model systems. This proposal therefore seeks to fully characterize the cellular effectors (receptors and binding proteins) of the IGF system, and to use these observations to develop feasible therapeutic strategies for inhibiting IGF-Medicated breast cancer proliferation.